Targeting IFN-γ ameliorates cytotoxic responses in retinal degenerative disease and enhances long-term functional engraftment of hESC-derived RPE cells transplantation
Purpose
To investigate the impacts of pro-inflammatory T cells in the etiology of age-related macular degeneration (AMD) pathogenesis.
Methods
Flow cytometry was performed to decect the frequencies of different T cell subsets in the PBMCs from AMD patients and healthy controls. Integrative analysis of single-cell RNA-sequencing (scRNA-seq) and proteomic profiling were performed to assess the retinal and peripheral micro-environment of AMD patients. AMD PBMCs primed hESC-RPE cells were used to mimic diseased retinal microenvironment for in vitro and drug screening experiments.
Results
Increased Th1 cell frequency was detected in the PBMCs from AMD patients, along with increased infiltration of IFN-γ producing CD4+/CD8+ T lymphocytes as well as NK cells. The results of scRNA-seq and proteomic profiling further confirmed activation of IFN-γ signaling and involvement of T/NK cells in the peripheral blood and retina from AMD patients. IFN-γ could trigger JAK signaling activation and enhance antigen processing and presenting via HLA expression, eventually leading to T/NK cell mediated cytotoxic response. JAK1 signaling FDA approved JAK1/2 inhibitor-ruxolitinib could hinder the cytotoxicity responses and improve the engraftment of hESC-RPE cells into degenerated retina.
Conclusion
Our work elucidates the role of IFN-γ in AMD and introduces an approach for suppressing cytotoxicity responses and allograft rejection in an IFN-γ-specific manner, showing potential applications for hESC-derived cell replacement therapy without systemic immune suppression, with a promising view to successful clinical outcomes.
Conflict of interest
No
Authors 1
Last name
GAO
Initials of first name(s)
Y
Department
Southwest Hospital，Army Medical University
City
Chongqing
Country
China
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